Injury to one part of the body often results in hypersensitivity to painful stimuli. It has recently been discovered that this phenomenon is not, as previously thought, driven only by transmission of nerve impulses from a site of peripheral inflammation through the spinal cord to the brain. Rather, Samad, et al. have opined that hyperalgesia results from facilitation of pain processing signals inside the brain and spinal cord. Samad, et al., Nature 410, 471-475 (2001).
One theory as to how such signalling occurs posits that an increase in cerebrospinal levels of interleukin-1β may signal the central nervous system that an injury to the body has occurred. Eck, et al. have suggested that interleukin-1β may interact with cells at the blood-brain barrier to stimulate expression of cyclooxygenase-2 and prostaglandin E synthase. Eck, Nature 410: 430-431 (2001).
Following hydrolysis of arachidonic acid from phospholipid by phospholipase A2, cyclooxygenase-2 converts arachidonic acid into prostaglandin H2. In turn, prostaglandin E synthase converts prostaglandin H2 into prostaglandin E2, a potent inflammatory mediator. Prostaglandin E2 also activates the synthesis of interleukin-1β by microglia (possibly explaining the latter's presence in cerebrospinal fluid).
Whatever the specific mechanism, the end product of the central cyclooxygenase signaling cascade is enhanced pain and inflammation.
To date, therapeutic proposals to target the cyclooxygenase signalling cascade to treat hyperalgesia have focused on inhibition of cyclooxygenase-2 activity. See, e.g., Bartfai, T., Nature 410: 425-427 (2001); referencing Samad, et al. and Eck, supra. However, current pain remedies and anti-inflammatories commonly employed to this end are either potentially addictive opiates or are non-steroidal anti-inflammatories (NSAIDS) designed to target the cyclooxygenase enzymes (e.g., aspirin, ibuprofen, ketorolac, Celebrex™ and Vioxx™). Cyclooxygenase-2 is also the target of most antipyretic (fever-reducing) drugs.
Phospholipase A2 (PLA2) has not received much attention as a therapeutic target in the cyclooxygenase signaling cascade. To the contrary, it has been reported that no increase in PLA2 activity in the spinal cord or brain is produced in response to peripheral injury in an animal model (rat paw edema). See, e.g., Samad, et al., at 471 and 473, FIG. 2, which recently concluded that “COX-2 [cyclooxygenase-2] alone appears to be pivotal in central [nervous system] PGE2 induction.” Id., at 471.